Bispecific antibodies that bind to CD38 and CD3

Active Publication Date: 2020-12-08
XENCOR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0079]FIG. 34 depicts a schematic associated with the use of separation variants, also referred to herein as “pI variants”, and combined with the heterodimer assembly variants, also referred to herein as “skew variants”. These variants can be used in a “plug and play” format, in that the effects of the variants transfer into different antibodies with different Fv region

Problems solved by technology

While these formats can be expressed at high levels in bacteria and may have favorable penetration benefits due to their small size, they clear rapidly in vivo and can present manufacturing obstacles related to their production and stability.
A principal cause of these drawbacks is that antibody fragments typically lack the constant region of the antibody with its associated functional properties, including larger size, high stability, and binding to various Fc receptors and ligands that maintain long half-life in serum (i.e., the neonatal Fc receptor FcRn) or serve as binding sites for purification (i.e., protein A and protein G).
One significant drawba

Method used

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  • Bispecific antibodies that bind to CD38 and CD3
  • Bispecific antibodies that bind to CD38 and CD3
  • Bispecific antibodies that bind to CD38 and CD3

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1. Prototype “Triple F” Bispecific Antibody

[0346]The present invention describes novel immunoglobulin compositions that co-engage a first and second antigen. One heavy chain of the antibody contains a single chain Fv (“scFv”, as defined herein) and the other heavy chain is a “regular” Fab format, comprising a variable heavy chain and a light chain (see FIG. 1). This structure is sometimes referred to herein as “triple F” format (scFv-Fab-Fc). The two chains are brought together by the dimeric Fc region (see FIG. 2). The Fc region can be modified by amino acid substitution to allow for efficient purification of the “triple F” heterodimer. Further, the Fc region can be modified by amino acid substitution to promote the formation of the “triple F” heterodimer. Examples of Fc substitutions are described more fully below.

[0347]Fc substitutions can be included in the “triple F” format to allow for efficient purification of the desired “triple F” heterodimer over the undesired dual...

Example

Example 2. Multi-Specific Antibodies Derived from the “Triple F” Format

[0350]Multi-specific antibodies can be constructed by attaching additional scFv or Fab domains that bind a third antigen to the C-terminus of one of the “triple F” heavy chains. See FIG. 5 for examples. Alternatively, the C-terminal scFv or Fab may bind the first or second antigen, thus conferring bivalency and an increase in overall binding affinity for that antigen.

[0351]Multi-specific antibodies can also be constructed by coupling the scFv-Fc heavy chain of the “triple F” format may with rearranged antibody heavy chains as depicted in FIG. 6. Such rearranged heavy chains may include an additional Fv region that binds a third antigen or an additional Fv region that binds the first antigen or second antigen, thus conferring bivalency and an increase in overall binding affinity for that antigen.

Example

Example 3. Anti-CD19 Fab×Anti-CD3 scFv “Triple F” Bispecific

[0352]Amino acid sequences for anti-CD19 Fab×anti-CD3 scFv “triple F” bispecifics are listed in the figures. Amino acid substitutions made to allow for efficient purification of the desired “triple F” heterodimer over the undesired dual scFv-Fc and mAb homodimers are underlined. Amino acid sequences for preferred humanized anti-CD3 variable regions are listed in FIGS. 2 and 6 (with CDRs underlined). Some examples of expression and purification of the desired “triple F” species and its bioactivity are given below.

[0353]The production of XENP11874, a “triple F” bispecific with an anti-CD 19 Fab and anti-CD3 scFv, is outlined in FIG. 9. In FIG. 9A, the ion exchange purification of the desired “triple F” heterodimer from the undesired dual scFv-Fc and mAb homodimers is shown. The purity of the “triple F” fraction was checked by IEF gel, (data shown in FIG. 9B of U.S. Ser. No. 61 / 818,410, all figures and legends of which are exp...

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Abstract

The invention provides novel heterodimeric proteins including heterodimeric antibodies.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 673,695 filed Mar. 30, 2015, which in turn claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Applications Nos. 61 / 972,172, filed Mar. 28, 2014, 62 / 025,974, filed Jul. 7, 2014, and 62 / 025,931, filed Jul. 17, 2014, the entire contents of which are incorporated herein for all purposes by this reference and specifically for the figures, legends and data outlined herein.INCORPORATION BY REFERENCE OF A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB[0002]This application contains, as a separate part of disclosure, a Sequence Listing in computer-readable form (filename: 50362A_Seqlisting.txt; Size: 934,047 bytes; created Jan. 22, 2020), which is incorporated by reference in its entirety.TECHNICAL FIELD[0003]The present invention describes novel immunoglobulin compositions that simultaneously co-engage antigens, where both of the antigens are bound mono...

Claims

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Application Information

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IPC IPC(8): C07K16/40C07K16/30C07K16/18A61K39/00C07K16/46C07K16/28
CPCC07K16/2809C07K16/468C07K16/2896C07K16/30C07K2317/64C07K2317/622C07K2317/31C07K2317/24C07K2317/55C07K2317/73C07K2317/52C07K2317/94C07K2317/565C07K2317/92A61P31/00A61P35/00A61K2039/505A61K39/395
Inventor BERNETT, MATTHEW J.CHU, SEUNG Y.MOOREDESJARLAIS, JOHN
Owner XENCOR
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